Navigating Frontline BTKi Therapy: Considerations for TN CLL

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When selecting BTK inhibitor–based regimens for treatment-naive patients with chronic lymphocytic leukemia, oncologists must navigate between continuous monotherapy and combination strategies. Currently, no FDA-approved combination of covalent BTK inhibitors with BCL2 inhibitors exists for frontline use, making the promising CAPTIVATE trial data with ibrutinib plus venetoclax primarily investigational. The addition of obinutuzumab to acalabrutinib (elevate-TN data) shows continued progression-free survival benefits, but the IV administration adds complexity, treatment burden, and clinic time that many patients prefer to avoid.

Most patients favor the convenience of oral-only regimens when choosing continuous BTK inhibitor therapy over combination approaches requiring IV infusions. The AMPLIFY study data, although showing promise for oral BTK inhibitor-plus-venetoclax combinations, remain immature with limited follow-up. This creates uncertainty about long-term outcomes and optimal treatment duration for these newer fixed-duration approaches.

A critical knowledge gap exists regarding retreatment strategies after completion of fixed-duration BTK inhibitor combinations. Although CAPTIVATE trial data suggest that patients requiring retreatment respond well to BTK inhibitor monotherapy, the extrapolation of these findings to other combinations remains uncertain. This uncertainty underscores the need for longer follow-up data to better understand treatment-free intervals and retreatment outcomes in the era of novel oral combination therapies.